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Polyneuropathies Mononeuropathies Motoneuron diseases. Zsuzsanna Arányi. Peripheral nerve. Motor, sensory and autonomic fibers Fiber types according to diameter: A fibers- 1-17 μ m in diameter; myelinated motor and sensory fibers B fibers- 1-3 μ m in diameter; myelinated autonomic fibers

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peripheral nerve
Peripheral nerve
  • Motor, sensory and autonomic fibers
  • Fiber types according to diameter:
  • A fibers- 1-17 μm in diameter; myelinated motor and sensory fibers
  • B fibers- 1-3 μm in diameter; myelinated autonomic fibers
  • C fibers- 0.3-1.3 μm in diameter; non-myelinated autonomic and pain fibers
types of peripheral nerve damage
Types of peripheral nerve damage

Demyelination

  • Slowed conduction: no symptoms
  • Conduction block: weakness and sensory loss, but no atrophy

Axonal damage (axonotmesis)

  • Degeneration of axons distal to the lesion (denervation)
  • Weakness, sensory loss, atrophy

Neurotmesis

  • Damage to axons and epineurium
  • Weakness, sensory loss, atrophy
  • No regeneration without nerve suture
nerve regeneration reinnervation
Nerve regeneration – reinnervation

Remyelination

Proximo-distal

axon regeneration

Collateral reinnervation

(in case of partial nerve

damage)

2-12 weeks

1 mm/day

Intact basal

lamina/endoneuriumis needed

Starts within 4-6 weeks

polyneuropathies
Polyneuropathies
  • Generalised disease of the peripheral nervous system (nerve roots and peripheral nerves)
  • Usually the longest nerves are affected first
    • Symptoms start on the toes, feet
  • Usually the symptom of an underlying systemic disease
    • Search for etiology!
classification of polyneuropathies
Classification of polyneuropathies
  • Clinical presentation
    • Symmetric
    • Asymmetric
  • Time course
    • Acute
    • Chronic
  • Etiology
  • Pathology
    • Axonal
    • Demyelinative
    • Small-fiber
clinical forms of polyneuropathies
Clinical forms of polyneuropathies
  • Chronic, symmetric, distal and predominantly sensory polyneuropathies
  • Mononeuropathy multiplex
  • Purely motor or sensory polyneuropathies
  • Autonomic polyneuropathies
  • Acute polyneuropathies
typical symptoms of polyneuropathies
Typical symptoms of polyneuropathies
  • Chronic course
  • Symmetric, distal paraesthesia, pain and hypaesthesia in stocking – glove distribution; feet are affected first
  • Allodynia
  • Depressed or absent tendon reflexes
  • Distally pronounced muscle weakness, with wasting, fasciculation
  • Gait disorder
    • Sensory ataxia
    • Weakness
  • Autonomic dysfunction (reduced sweating, tachycardia, urinary disturbances, gastroparesis etc.)
typical complaints of patients with polyneuropathies
Typical complaints of patients with polyneuropathies
  • Tingling, pin-prick, numbness, burning or cold sensation, burning pain (especially during the night)
  • ‘Ants crawling on my legs’
  • ‘As if I had tight boots on’
  • ‘As if I were walking on a duvet’
  • ‘As if I had stockings on when really not’
  • ‘As if my skin were thick on my soles’
  • Unstable gait, ‘dizziness’
  • Loss of dexterity of the hands: ‘I drop objects’
causes of polyneuropathy
Causes of polyneuropathy
  • Metabolic-endocrine disturbances: diabetes mellitus, uremia etc.
  • Vitamin deficiencies: vitamin B1 -alcoholism, malabsorption, malnutrition, vitamin B12
  • Toxic causes: heavy metals, industrial solvents, drugs, alcohol
  • Dysimmune polyneuropathies
    • With manifestation only in the peripheral nervous system: acute inflammatory demyelinative polyneuropathy (Guillain-Barré syndrome), chronic inflammatory demyelinative polyneuropathy (CIDP), multifocal motor neuropathy (MMN)
    • Systemic diseases: vasculitis (polyarteritis nodosa, SLE etc.), paraproteinaemias
    • Paraneoplasia
  • Infectious: lepra, Lyme-disease, HIV
  • Hereditary: Charcot-Marie-Tooth disease etc.
  • Other: critical illness polyneuropathy, small-fiber neuropathy
  • Idiopathic
investigation of polyneuropathies
Investigation of polyneuropathies
  • ENG-EMG
  • Blood tests: We, blood count, glucose, hepatic and renal function
  • Vitamin B12
  • Thyroid function
  • Se electrophoresis, autoanti-bodies, cryoglobulin
  • Serological examinations (HIV, Lyme, HCV)
  • Search for tumors
  • CSF
  • Toxicological investigations
  • Sural nerve biopsy
  • Genetic tests
treatment of polyneuropathies
Treatment of polyneuropathies
  • Treat the cause!
  • Immune therapy
    • plasmapheresis: Guillain-Barré syndrome, CIDP
    • immunoglobulins: MMN, Guillain-Barré syndrome, CIDP
    • corticosteroids: CIDP, systemic vasculitis
  • Symptomatic treatment of paraesthesias and neuropathic pain
    • antiepileptic medications (carbamazepine, gabapentin, pregabalin)
    • tricyclic antidepressants (amitriptilin, clomipramin)
    • SNRI antidepressants (duloxetin, venlafaxin)
  • Vitamin B1: alcoholism, malabsorption, malnutrition
polyneuropathies associated with diabetes mellitus
Polyneuropathies associated with diabetes mellitus
  • Distal symmetric sensory polyneuropathy
  • Mononeuropathies- carpal tunnel syndrome, ulnar nerve lesion
  • Cranial nerve lesions- oculomotor nerve palsy
  • Autonomic neuropathy- sexual and urinary disturbance, gastroparesis and diarrhoea etc.
  • Diabetic amyotrophy- painful, asymmetric, proximal weakness (plexopathy?)
  • Radiculopathy- lumbar, thoraco-abdominal
diabetic chronic distal symmetric sensory polyneuropathy
Diabetic chronic distal symmetric sensory polyneuropathy
  • The most common form of diabetic neuropathy
    • Prevalence among diabetic patients: 20-60%
    • Present at the diagnosis of diabetes in 20% of patients
    • May be the only manifestation of impaired glucose tolerance
  • Severity is usually proportional to the duration and severity of hyperglycemia
  • Prevalence increases with age and duration of diabetes
  • Small fibers (pain, temperature, light touch) are preferentially affected →painful diabetic neuropathy in about 20-35%
  • Autonomic dysfunction
  • Trophic alterations →diabetic foot
small fiber neuropathy skin biopsy
Small fiber neuropathy- skin biopsy

NormalSmall fiber neuropathy

Epidermal nerve fibers (arrow): anti PGP 9.5 antibodies

Fibrous tissue and basal lamina: anti collagen IV antibodies

symptoms of sensory diabetic neuropathy i
Symptoms of sensory diabetic neuropathy I.
  • Length-dependent: first symptoms on the toes and feet
  • Later stocking-gloves distribution
  • Usually doesn’t go above the knees and elbows
  • If symptoms appear on the hands first → carpal tunnel syndrome
  • Areflexia
  • Trophic changes
symptoms of sensory diabetic neuropathy ii
Symptoms of sensory diabetic neuropathy II.
  • Positive sensory symptoms:
    • burning pain (pronounced during the night)
    • hyperesthesia, allodynia
    • paresthesia
  • Negative sensory symptoms:
    • hypesthesia (loss of sensation)
diabetic foot
Diabetic foot
  • Related to diabetic sensory neuropathy and peripheral artery disease
  • Diabetic foot ulcers precede 85% of non-traumatic lower limb amputations
  • Life-time prevalence of foot ulcers is 15% in diabetic patients
guillain barr syndrome
Guillain-Barré syndrome
  • Acute immunmodulated poly-radiculo-neuro-pathy
  • Pathology: perivascular lymphocyte-macrophage infiltration in the peripheral nervous system leading to macrophage mediated segmental demyelination
  • Incidence: 1.5-2.0/100 000/year
  • In most cases preceded by an infection (upper respiratory tract infection, diarrhoea)
  • Infectious agents associated with Guillain-Barré syndrome: CMV, EBV, HIV, Campylobacter jejuni, Mycoplasma pneumoniae
    • The infectious agent is usually unidentified
guillain barr syndrome symptoms
Guillain-Barré syndrome- symptoms
  • Acute, symmetric ascending flaccid paralysis
    • Variable severity
  • Respiratory insufficiency
  • Bilateral facial palsy
  • Ascending numbness to a lesser degree
  • Radicular pain
  • Areflexia
  • Autonomic symptoms- tachycardia, cardiovascular instability
guillain barr syndrome time course
Guillain-Barré syndrome- time course
  • Symptoms evolve over 1-2 weeks
  • Plateau is reached within 2-3 weeks
  • Spontaneous recovery within a few months
  • Good prognosis
    • Prognosis is determined mainly by complications of being bed-bound (infection, thrombosis etc.)
guillain barr syndrome diagnosis
Guillain-Barré syndrome- diagnosis

Normal neurography Segmental demyelination

Conduction block Temporal dispersion

guillain barr syndrome diagnosis and treatment
Guillain-Barré syndrome- diagnosis and treatment
  • Diagnosis
    • Clinical symptoms
    • Electroneurography- confirms segmental demyelination
    • Cerebrospinal fluid examination: elevated protein content with normal cell count (starting from the 2nd week)
  • Treatment
    • Plasmapheresis, immunoglobulin (IVIG)
    • Supportive treatment!
chronic inflammatory demyelinative polyneuropathy cidp
Chronic inflammatory demyelinative polyneuropathy (CIDP)
  • Autoimmune disease
  • Prevalence: 1-2/100 000
  • Course:
    • chronic monophasic (15%)
    • chronic relapsing-remitting (34%)
    • step-wise progressive (34%)
    • continuously progressive (15%)
  • Symptoms: proximal and distal motor and sensory symptoms, cranial symptoms (not a length-dependent neuropathy)
  • Rarely associated with central nervous system demyelination (3%)
diagnosis of cidp
Diagnosis of CIDP
  • ENG/EMG: segmental (non-uniform) demyelination
  • CSF: protein >45 mg/dl, cell count <10
  • Histology (biopsy): not obligatory, may be normal
    • chronic demyelination-remyelination may lead to Schwann-cell proliferation (‘onion bulb’ formation)
    • infiltration of inflammatory cells
  • MRI: hypertrophy of peripheral nerves and nerve roots, contrast enhancement
cidp nerve biopsy
CIDP- nerve biopsy

‘onion bulbs’

cidp mri
CIDP- MRI

Hypertrophied trigeminal nerves

cidp treatment
CIDP treatment
  • IVIG
    • 2 g/kg bw in 2-5 days, monthly for 3 months
    • maintanance treatment
  • Corticosteroids
    • methylprednisolon 1 mg/kg bw, later gradual reduction
  • Plasmapheresis
mononeuropathies causes
Mononeuropathies- causes
  • Trauma
    • cutting, laceration and stretching of the nerve
  • Compression
    • often iatrogenic
  • Tunnel syndromes
  • Ischemia
localisation of focal nerve lesions
Localisation of focal nerve lesions
  • A partial proximal nerve lesion may selectively affect only one nerve fascicle → clinically the lesion appears more distal
  • The longer axons are more sensitive to compression → distal symptoms are more pronounced
distal median nerve damage carpal tunnel syndrome
Distal median nerve damage: carpal tunnel syndrome
  • Incidence: 200-500/100 000/year, 3 times more common in women
  • Symptoms:
    • Painful paraesthesia of the hand during the night, pain in the whole arm
    • First the dominant hand is affected, but bilateral involvement in most cases
    • Advanced symptoms: sensory loss on digits 1-3, thenar atrophy and weakness
  • Causes: idiopathic, overuse, change of tunnel anatomy (fracture, arthrosis, oedema etc.), diabetes
  • Treatment:
    • Splinting of the hand during the night
    • Surgery
proximal median nerve damage
Proximal median nerve damage

1.

1. Weakness of all median nerve muscles ‘oath hand’

2.

2. Weakness of flexion of the distal phalanx of digit 1-2 no sensory loss

ulnar nerve lesion at the elbow two types
Ulnar nerve lesion at the elbow- two types

Extension

Flexion

  • Retroepicondylar lesion (more common)
    • Compression, elbow fracture, arthrosis, diabetes
  • Real cubital tunnel syndrome
ulnar nerve lesion
Ulnar nerve lesion
  • Numbness of digit 4-5 and ulnar edge of the hand
  • Atrophy and weakness of hypothenar, interosseus muscles and adductor pollicis muscle
  • Tinel-sign at the elbow
  • Claw hand
radial nerve lesion on the upper arm
Radial nerve lesion on the upper arm
  • ‘Saturday night palsy’: nerve compression during sleep
    • common in alcoholics
  • Symptoms: weakness of wrist and finger extension (wrist drop); triceps is normal;loss of sensation on the dorsal-radial aspect of the hand
radial nerve lesion on the forearm
Radial nerve lesion on the forearm
  • Weakness of finger extension (‘finger drop’), extension of the wrist is only sightly weak, oftens starts on digit 4-5 → may be confused with ulnar nerve lesion
  • No sensory loss
  • Causes: supinator tunnel syndrome due to overuse
peroneal nerve damage at the fibular head
Peroneal nerve damage at the fibular head
  • Foot drop, steppage gate
  • Supination (inversion) and plantarflexion is normal
  • Sensory loss on the lateral aspect of the leg and dorsal aspect of the foot
  • Causes: compression
    • During sleep, in coma
    • During surgery
    • Cast
    • Crossed legs
    • Squatting (strawberry pickers)
    • Peroneal tunnel syndrome?
motoneuron diseases
Motoneuron diseases
  • Progressive loss/degeneration of motoneurons
    • Weakness
    • Atrophy
    • No sensory or autonomic symptoms
  • Two major types:
    • Amyotrophic lateralsclerosis (ALS): both upper and lower motoneurons are affected
    • Spinal muscular atrophies / lower motoneuron syndromes
slide44
ALS

First described by Jean Martin Charcot in 1874

  • Incidence: 2 / 100 000 / year
  • Prevalence: 6 / 100 000

‘Lou Gehrig’s disease’

als clinical forms
ALS- Clinical forms
  • Sporadic ALS
    • Classic ALS
    • Progressive muscular atrophy (PMA)
    • Primary lateralsclerosis
    • Progressive bulbar paralysis
    • Progressive pseudobulbar palsy
  • Familial ALS (5-10%)
    • Autosome dominant
      • SOD1 mutations
      • No SOD1 mutations
    • Autosome recessive
      • SOD1 mutation
      • Chronic juvenile ALS
    • X-linked
  • Frontotemporal dementia+ ALS (ubiquitin positive)

Progressive

muscular

atrophy (PMA)

Lower

motoneuron

onset

Classic ALS

Upper

motoneuron

onset

Bulbar onset

Progressive

bulbar

paralysis

Primary

lateralsclerosis

als symptoms and course
ALS- symptoms and course
  • Mixed signs of upper and lower motor neuron lesion
    • Atrophy, fasciculation, cramps
    • Spasticity, increased reflexes, Babinski
  • Relentlessly and quickly progressive
  • Average survival: 2-5 years
    • Cause of death: respiratory insufficiency
als clinical syndromes at onset
ALS- Clinical syndromes at onset
  • Asymmetric small hand muscle atrophy and weakness (segmental distribution)- 60-85%
    • Diff. dg.: radiculopathy, ulnar nerve lesion
  • Proximal arm muscle atrophy and weakness (‘flail’ arm)
    • Diff. dg.: radiculopathy
  • Bulbar onset- 15-40%
    • Dysarthria and dysphagia
    • Diff. dg.: myasthenia gravis, pseudobulbar paresis
  • Spastic paraparesis
    • Diff. dg: spinal disease
als treatment
ALS- treatment
  • No cure
  • Only drug approved for ALS: riluzol (inhibits the presynaptic release of glutamate), survival on riluzol increases by 3-6 months
  • Supportive treatment:
    • Muscle relaxants
    • Antidepressants, anxiolytic drugs
    • PEG in case of severe dysphagia
    • Assistive devices
    • Ventilation??? (moral issue)

Riluzol trials

infantile and juvenile spinal muscular atrophies sma i iii
Infantile and juvenile spinal muscular atrophies (SMA I-III)
  • 1 / 6-20 000 live births
  • Autosome recessive
  • In 95% of patients the mutation is found in the SMN (survival motoneuron) gene (chr. 5)
infantile and juvenile spinal muscular atrophies sma i iii1
Infantile and juvenile spinal muscular atrophies (SMA I-III)
  • SMA I: Werdnig-Hoffmann disease. Symptoms are present at birth- ‘floppy baby’. Death within 1-2 years.
  • SMA II.: Intermediate form
  • SMA III: Kugelberg-Welander disease
    • Symptoms start at age 12-15 years: proximal, symmetric weakness in the legs
    • Progression is variable
    • Differential diagnosis: muscle dystrophies
    • Dg.: EMG (chronic neurogenic findings), genetic testing
adult onset spinal muscular atrophies lower motoneuron diseases
Adult onset spinal muscular atrophies / lower motoneuron diseases

SMA IV: \'adult onset\' proximal spinal muscular atrophy

  • Onset: 20-40 years of age
  • Inheritance: 70% AR, 30% AD
  • Gene is unknown
  • Symptoms: very slowly progressive limb girdle weakness and atrophy. May be asymmetric, the quadriceps muscle is very often affected. No bulbar involvement.
  • Differential diagnosis: muscle dystrophies, ALS
adult onset spinal muscular atrophies lower motoneuron diseases1
Adult onset spinal muscular atrophies / lower motoneuron diseases

dSMA V: \'adult onset\' distal spinal muscular atrophy

  • Onset: 20-40 years of age
  • Inheritance : AD
  • Gene is unknown
  • Symptoms : slowly progressive distal weakness and atrophy
  • Differential diagnosis: polyneuropathies
adult onset spinal muscular atrophies lower motoneuron diseases2
Adult onset spinal muscular atrophies / lower motoneuron diseases

Benign focal amyotrophy

  • Usually sporadic
  • More common in men
  • Starts in young adulthood, slow progression over a few years, then stagnation
  • Symptoms: small hand atrophy on one side
  • Differential diagnosis: ALS, ulnar nerve lesion
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